Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
  • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
  • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

• This invention relates to a novel 4-pyridyl-dihydropyridine derivative. More particularly, it is concerned with a 4-pyridyl-dihydropyridine derivative having an activity such as calcium-antagonism, blood pressure lowering and phosphodiesterase inhibition.
• An object of this invention is to provide a dihydropyridine derivative and the innoxious salt thereof, which have a more excellent pharmacological activity.
• Another object of this invention is to provide a pharmaceutical composition comprising a dihydropyridine derivative having an excellent pharmacological activity.
• This invention provides a novel dihydropyridine derivative (I) represented by the general formula wherein R 1 and R 2 are the same as or different from each other and denote each hydrogen, provided that they cannot be hydrogen at the same time, or a nitro, cyano, halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, alkylmercapto, alkylsulfinyl or alkylsulfonyl; R 3 , R 4 and R 5 denote independently an alkyl; R 6 and R7 independently denote hydrogen or alkyl or aralkyl which may be optionally substituted with halogen, or form a heterocyclic ring jointly with the adjacent nitrogen atom; X denotes a group -COO-; and A denotes an alkylene group; and an innoxious salt thereof.
• R 1 and R 2 are the same as or different from each other and denote each hydrogen, provided that they cannot be hydrogen at the same time, or a nitro
• the present compounds have such an excellent Ca-antagonistic activity, antihypertensive effect, thrombocyte agglutination inhibition effect and phosphodiesterase inhibition effect and are useful as a medicine, for example as a coronary vessel vasodilator, celebral blood flow increasing agent, antihypertensive agent, preventive or curative agent for thrombosis, and phosphodiesterase inhibitor.
• this invention provides a pharmaceutical composition useful for treating vascular disorders such as coronary and cerebral artery diseases comprising at least one dihydropyridine derivative (I) or innoxious salt thereof.
• the dihydropyridine derivative (I) of this invention has a unique structure as compared with the prior dihydropyridine compounds known in the art and hence has a unique activity originating from the structure.
• the dihydropyridine derivative (I) of this invention has a high organ and tissue selectivity, particularly in vasodilating action, and hence can attain an excellent pharmacological effect at a relatively small dose. As a result, it is characterized by its reduced systemic side effects.
• halogen or halogenated means fluorine, chlorine, bromine and iodine, or their substituent. Preferably, it is fluorine, chlorine, and bromine, and preferably fluorine and bromine for R 1 and R 2 .
• Alkyl may be either of straight chain or branched chain and includes, for example, alkyls of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl and preferably methyl for R 3 , R 4' and R 5 .
• Aralkyl groups include phenyl C 1 - C 3 alkyl group, for example, benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and 1-phenylpropyl, the said phenylgroup being optionally substituted with substituents such as an alkyl and halogen, among which benzyl is preferred for R 6 or R 7 .
• Alkylene groups have preferably 2 to 4 carbon atoms, may be either of straight chain or branched chain and include, for example, ethylene, trimethylene, propylene, tetramethylene, and 1,2-dimethylethylene group, and preferably ethylene group.
• the alkyl moiety and halogen in the alkoxy, halogenated alkyl, alkylmercapto, alkylsulfinyl, and alkylsulfonyl group for R 1 or R 2 are the same as the above-defined alkyl and halogen.
• the halogenated alkyl may be those in which a part of their hydrogen atoms have been halogenated [(CF 3 )2CHCH2-, CF 3 CH 2 - etc.] or those in which all of the hydrogen atoms have been halogenated (trifluoromethyl etc.), and trifluoromethyl is preferable for R 1 or R 2 .
• the halogenated alkoxy may be either those in which a part of their hydrogen atoms have been halogenated or those in which all of the hydrogen atoms have been halogenated.
• the heterocyclic ring formed by R 6 and R 7 together with adjacent nitrogen atom may contain an additional hetero atom.
• hetero atoms include an oxygen, a nitrogen and a sulfur atom.
• the heterocyclic ring include pyrrolidine, piperidine, morpholine, piperazine, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, imidazole, indole, isoindole, and benzimidazole.
• the heterocyclic ring may be optionally substituted by alkyl, aralkyl, halogen etc., which are the same as the above.
• the position of pyridyl group to be connected at the 4-position of dihydropyridine is preferably the 2-, 3-, or 4-position thereof; and the position of the substituent R 1 or R 2 , which are not hydrogen, may preferably be at a position next or next but one to the bond site of the pyridyl group with the dihydropyridyl group. Further, the relative position of the R 1 and the R 2 when both are present, is next, next but one or next but two to each other.
• the compounds (II), (III) and (IV) are first reacted in an appropriate solvent to prepare the compound (V).
• This reaction is carried out usually at about 30°C to 150°C, preferably about 50°C to 120°C, and particularly when the solvent used boils in the above-mentioned temperature range, at the boiling point.
• the solvent to be used is not particularly limited so long as it is inert to the reaction and includes, for example, alcohols such as methanol, ethanol, propanol, and isopropanol; ethers such as tetrahydrofuran, dioxane, and dimethoxyethane; N,N-dimethylformamide, dimethylsulfoxide, and acetonitrile.
• the reaction usually requires 1 to 20 hours for completion.
• amount of the compounds (II), (III) and (IV) to be used for 1 mole of any one of the three compounds 1 to 1.5 moles of each of the other two compounds is used.
• the starting compound (II) is already known or can be prepared by a known method [cf., for example, J, Am. Chem. Soc., 67, 1017 (1945)].
• the compound (IV) is already known or can be prepared by a known method [cf., for example, Chem. Pharm. Bull., 27 (6), 1426 (1979)].
• the various substituted pyridine aldehyde (II I ) can be obtained by preparing the pyridine alcohol shown below by a known method and then oxidizing it with, for example, dimethylsulfoxide (DMSO) - dicyclohexylcarbodiimide (DCC) - phosphoric acid.
• DMSO dimethylsulfoxide
• DCC dicyclohexylcarbodiimide
• the starting compound (VI) to be used in this method can be prepared by treating the starting compound (IV) used in the method A with the said secondary amine.
• a suitable solvent for example, ethanol, dioxane, tetrahydrofuran, N,N-dimethylformamide
• the novel dihydropyridine derivative (I) thus prepared can be recovered by optional means of separation and purification, for example, concentration, extraction, chromatography, reprecipitation and recrystallization, to collect a product in desired purity. Further, since the dihydropyridine derivative (I) has a basic group, it can also be converted to an acid addition salt by a conventional method.
• acid addition salts are not particularly limited so long as they are pharmaceutically acceptable and innoxious, and include, for example, inorganic acid salts (such as hydrochloride, hydrobromide, phosphate and sulfate) and organic acid salts (such as acetate, succinate, maleate, fumarate, malonate and tartrate).
• the dihydropyridine derivative (I) and its innoxious salt according to this invention are of low toxicity, exert a strong and long-lasting blood pressure depressing action, peripheral blood vessel vasodilating action, coronary artery vasodilating action and celebral blood vessel vasodilating action on mammals such as mice, rats, rabbits, dogs, cats, and humans, and are useful as, for example, a preventive or curative agent for diseases of circulatory systems in humans, for example, hypertension, ischemic cardiac diseases (e.g. angina pectoris and myocardial infarction), and cererbral and peripheral circulatory disorders (e.g. cerebral infarction and transient cerebral ischemic attack).
• ischemic cardiac diseases e.g. angina pectoris and myocardial infarction
• cererbral and peripheral circulatory disorders e.g. cerebral infarction and transient cerebral ischemic attack.
• the dihydropyridine derivative (I) or its innoxious salt are used as the above-mentioned medicaments, they can be mixed with such pharmaceutically necessary ingredients as appropriate, pharmaceutically compatible carriers, additives, and diluents and made up into pharmaceutical compositions in the form of powders, granules, tablets, capsules, and injectable compositions, to be administered orally or parenterally.
• the above-mentioned pharmaceutical preparations contain an effective amount of the dihydropyridine derivative (I) incorporated therein.
• the dosage varies depending upon the route of administration, the conditions, weight or age of patients, and other factors. In oral administration to adult hypertension patients for example, it is preferably administered at a dose of 0.05 to 20 mg/kg body weight/day, more preferably 0.1 to 4 mg/kg body weight/day, divided in 1 to several times per day.
• mice The results (LD 50 ) of acute toxicity test of the present Ca-antagonist (P.O.) in mice are 650-950 mg/kg.
• the compound to be tested was orally administered (at a dose of 25 mg/kg in terms of the active compound) as a 10% HCO-60 (polyoxyethylene hardened castor oil) suspension. Blood pressure was determined 1, 4 and 7 hours after the administration. Table 1 shows the respective average value of the blood pressure (in mmHg).
• Example 28 Further, the blood pressure depression effect of the fumarate of the compound obtained in Example 28 described later was examined in the same manner as described above. The result obtained showed that the maximum depression value (%) of blood pressure from the value (100%) before administration was 67%, and the time required for 50% recovery from maximum depression value (%) of blood pressure was 16.2 hours.
• reaction solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [silica gel; ethyl acetate-n-hexane (5 : 6)].
• the crude product thus obtained was recrystallized from isopropyl ether-methanol to obtain 1.546 g (34% yield) of the above-captioned compound.
• Example 2 The objective compound obtained in Example 1 (858 mg, 1.86 mmol) and fumaric acid (216 mg, 1.86 mmol) were dissolved in 25 ml of ethanol, and the solution was stirred at room temperature for 70 minutes. The reaction solvent was distilled off under reduced pressure to obtain 1.07 g of the fumaric acid salt of the compound.
• the object compound (1.037 g, 2.02 mmol) obtained in Example 3 and fumaric acid (234 mg, 2.02 mmol) were dissolved in 24 ml of ethanol, and the solution was stirred at room temperature for 4 hours.
• the reaction solvent was distilled off under reduced pressure to obtain 1.2 g of the fumaric acid salt of the compound.
• Example 2 The same procedures as those in Example 1 were followed by using 4-nitro-2-pyridine aldehyde in place of 6-cyano-2-pyridine aldehyde to obtain the compound in 25% yield (m.p.: 163°C, methanol).
• the above ingredients were mixed with starch to obtain 300 mg of a tablet preparation, according to a conventional tablet preparation method.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Hydrogenated Pyridines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1986
  • 1986-09-02 DE DE8686306770T patent/DE3682857D1/de not_active Expired - Lifetime
  • 1986-09-02 EP EP86306770A patent/EP0216542B1/fr not_active Expired - Lifetime
  • 1986-09-05 CA CA000517525A patent/CA1295331C/fr not_active Expired - Lifetime
  • 1986-09-09 US US06/906,268 patent/US4849429A/en not_active Expired - Fee Related
  • 1986-09-12 ES ES8601837A patent/ES2002325A6/es not_active Expired
  • 1986-09-13 KR KR1019860007724A patent/KR870003094A/ko not_active IP Right Cessation

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